Aryl aminopyridine PDE10 inhibitors

ABSTRACT

The present invention is directed to aryl aminopyridine compounds which are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDE10). The present invention also relates to the use of such compounds for treating neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington&#39;s disease, and those associated with striatal hypofunction or basal ganglia dysfunction.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/US2010/054009, filed Oct. 26, 2010, which claims priority under 35 U.S.C. §119(e) from U.S. Ser. No. 61/256,466 filed Oct. 30, 2009.

FIELD OF THE INVENTION

The invention relates generally to compounds which act as inhibitors of the phosphodiesterase (PDE) 10 enzyme, compositions and therapeutic uses thereof.

BACKGROUND OF THE INVENTION

Schizophrenia is debilitating disorder affecting the psychic and motor functions of the brain. It is typically diagnosed in individuals in their early to mid-twenties and symptoms include hallucinations and delusions or at the other extreme, anhedonia or social withdrawal. Across the spectrum, the symptoms are indicative of cognitive impairment and functional disabilities. Notwithstanding improvements in antipsychotic treatments, current therapies, including typical (haloperidol) and atypical (clozapine or olanzapine) antipsychotics, have been less than acceptable and result in an extremely high rate of noncomplicance or discontinuation of medication. Dissatisfaction with therapy is attributed to lack of efficacy or intolerable and unacceptable side affects. The side effects have been associated with significant metabolic, extrapyramidal, prolactic and cardiac adverse events. See, Lieberman et al., N. Engl. J. Med. (2005) 353:1209-1223.

While multiple pathways are believed to be involved with the pathogenesis of schizophrenia leading to psychosis and cognition deficits, much attention has focused on the role of glutamate/NMDA dysfunction associated with cyclic guanosine monophasphate (cGMP) levels and the dopaminergic D2 receptor associated with cyclic adenosine monophosphate (cAMP). These ubiquitous second messengers are responsible for altering the function of many intracellular proteins. Cyclic AMP is thought to regulate the activity of cAMP-dependent protein kinase (PKA), which in turns phosphorylates and regulates many types of proteins including ion channels, enzymes and transcription factors. Similarly, cGMP is also responsible for downstream regulation of kinases and ion channels.

One pathway for affecting the levels of cyclic nucleotides, such as cAMP and cGMP, is to alter or regulate the enzymes that degrade these enzymes, known as 3′, 5′-cyclic nucleotide specific phosphodiesterases (PDEs). The PDE superfamily includes twenty one genes that encode for eleven families of PDEs. These families are further subdivided based on catalytic domain homology and substrate specificity and include the 1) cAMP specific, PDE4A-D, 7A and 7B, and 8A and 8B, 2) cGMP specific, PDE 5A, 6A-C, and 9A, and 3) those that are dual substrate, PDE 1A-C, 2A, 3A and 3B, 10A, and 11A. The homology between the families, ranging from 20% to 45% suggests that it may be possible to develop selective inhibitors for each of these subtypes.

The identification of PDE 10 was reported by three groups independently and was distinguished from other PDEs on the basis of its amino acid sequence, functional properties, and tissue distribution (Fujishige et al., J. Biol. Chem. (1999) 274:18438-18445; Loughney et al., Gene (1999) 234: 109-117; Soderling et al., PNAS, USA (1999) 96: 7071-7076). The PDE10 subtype at present consists of a sole member, PDE10A, having alternative splice variants at both the N-terminus (three variants) and C-terminus (two variants), but that does not affect the GAF domain in the N-terminus or the catalytic site in C-terminus. The N-terminus splice variants, PDE10A1 and PDE10A2, differ in that the A2 variant has a PKA phosphorylation site that upon activation, i.e. PKA phosphorylation in response to elevated cAMP levels, results in intracellular changes to the localization of the enzyme. PDE10A is unique relative to other PDE families also having the conserved GAF domain in that its ligand is cAMP, while for the other GAF-domain PDEs the ligand is cGMP (Kehler et al., Expert Opin. Ther. Patents (2007) 17(2): 147-158). PDE10A has limited but high expression in the brain and testes. The high expression in the brain and, in particular, the neurons of the striatum, unique to PDE10, suggests that inhibitors thereto may be well suited from treating neurological and psychiatric disorders and conditions.

Inhibition of PDE10 is believed to be useful in the treatment of schizophrenia and a wide variety of conditions or disorders that would benefit from increasing levels of cAMP and/or cGMP within neurons, including a variety neurological, psychotic, anxiety and/or movement disorders. Accordingly, agents that inhibit PDE10 and especially PDE10A would be desirable as therapeutics for neurological and psychiatric disorders.

SUMMARY OF THE INVENTION

The present invention is directed to aryl aminopyridine compounds which are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDE10). The present invention also relates to the use of such compounds for treating neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington's disease, and those associated with striatal hypofunction or basal ganglia dysfunction.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein: X is —CH— or N, Y is —CH— or N, and Z is —CH— or N, with the proviso that at least one of X, Y and Z is N; R¹ is selected from the group consisting of:

-   -   (1) hydrogen,     -   (2) halogen,     -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl, or phenyl, and     -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl or phenyl;         R^(2a), R^(2b) and R^(2c) are independently selected from the         group consisting of     -   (1) hydrogen,     -   (2) halogen,     -   (3) hydroxyl,     -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl, phenyl or napthyl,     -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl or phenyl,     -   (6) phenyl, which is unsubstituted or substituted with halogen,         hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or         substituted with fluoro,     -   (7) heteroaryl, which is unsubstituted or substituted with         halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro,     -   (8) —O—-phenyl, which is unsubstituted or substituted with         halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro,     -   (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl) which is         unsubstituted or substituted with halogen, hydroxyl,         —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted         with fluoro,     -   (10) —CO₂H,     -   (11) —CN, and     -   (12) —NO₂,     -   or R^(2a) and R^(2b) may be joined together to form a phenyl,         pyridyl or piperidinyl ring, which is unsubstituted or         substituted with R^(2c);         R³ and R⁴ are independently selected from the group consisting         of:     -   (1) hydrogen, and     -   (2) C₁₋₆alkyl, which is unsubstituted or substituted with R¹⁴,     -   or R³ and R⁴ may be joined together to form a heterocyclyl,         which is unsubstituted or substituted with halogen, hydroxyl,         phenyl, pyridyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with halogen, hydroxyl or phenyl;         R¹⁴ is selected from the group consisting of:     -   (1) hydroxyl,     -   (2) halogen,     -   (3) C₁₋₆alkyl,     -   (4) —C₃₋₆cycloalkyl,     -   (5) —O—C₁₋₆alkyl,     -   (6) —O(C═O)—C₁₋₆alkyl,     -   (7) ═O,     -   (8) —CO₂,     -   (9) —CO₂—C₁₋₆alkyl,     -   (10) —NH(C═O)—C₁₋₆alkyl, —N(C₁₋₆alkyl)(C═O)—C₁₋₆alkyl,         —NH(C═O)—O—C₁₋₆alkyl, —N(C₁₋₆alkyl)(C═O)—O—C₁₋₆alkyl, which is         unsubstituted or substituted with halogen, hydroxyl,         —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted         with fluoro,     -   (11) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)—C₁₋₆alkyl, which is         unsubstituted or substituted with halogen, hydroxyl,         —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted         with fluoro,     -   (12) phenyl, which is unsubstituted or substituted with halogen,         hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or         substituted with fluoro,     -   (13) heteroaryl, which is unsubstituted or substituted with         halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro,     -   (14) heterocyclyl, which is unsubstituted or substituted with         halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro, and     -   (15) —CN;         or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ia:

wherein R¹, R^(2a), R^(2b), R^(2c), R³ and R⁴ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ia′:

wherein R¹, R^(2a), R^(2b), R^(2c), R³ and R⁴ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ia″:

wherein R¹, R^(2a), R^(2b), R^(2c), R³ and R⁴ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ib:

wherein R¹, R^(2a), R^(2b), and R^(2c) are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ib′:

wherein R¹, R^(2a), R^(2b), and R^(2c) are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ib″:

wherein R¹, R^(2a), R^(2b), and R^(2c) are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ic:

wherein R¹, R^(2a), R^(2b), and R^(2c) are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ic′:

wherein R¹, R^(2a), R^(2b), and R^(2c) are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ic″:

wherein R¹, R^(2a), R^(2b), and R^(2c) are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Id:

wherein R¹, R^(2a), R^(2b), and R^(2c) are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Id′:

wherein R¹, R^(2a), R^(2b), and R^(2c) are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Id″:

wherein R¹, R^(2a), R^(2b), and R^(2c) are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds wherein X is N, Y is —CH—, and Z is —CH—. An embodiment of the present invention includes compounds wherein X is X is —CH—, Y is —N, and Z is —CH—. An embodiment of the present invention includes compounds wherein X is —CH—, Y is —CH—, and Z is N. An embodiment of the present invention includes compounds wherein X is N, Y is —CH—, and Z is N.

An embodiment of the present invention includes compounds wherein R¹ is selected from the group consisting of:

-   -   (1) hydrogen, and     -   (2) halogen.

An embodiment of the present invention includes compounds wherein R¹ is selected from the group consisting of:

-   -   (1) hydrogen, and     -   (2) fluoro.

An embodiment of the present invention includes compounds wherein R¹ is hydrogen.

An embodiment of the present invention includes compounds wherein R^(2a), R^(2b) and R^(2c) are independently selected from the group consisting of:

-   -   (1) hydrogen,     -   (2) halogen,     -   (3) hydroxyl,     -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl, phenyl or napthyl,     -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl or phenyl,     -   (6) phenyl, which is unsubstituted or substituted with halogen,         hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or         substituted with fluoro,     -   (7) heteroaryl, which is unsubstituted or substituted with         halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro,     -   (8) —O-phenyl, which is unsubstituted or substituted with         halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro,     -   (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is         unsubstituted or substituted with halogen, hydroxyl,         —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted         with fluoro,     -   (10) —CO₂H,     -   (11) —CN, and     -   (12) —NO₂,     -    or R^(2a) and R^(2b) may be joined together to form a phenyl,         pyridyl or piperidinyl ring, which is unsubstituted or         substituted with R^(2c).

An embodiment of the present invention includes compounds wherein R^(2a), R^(2b) and R^(2c) are independently selected from the group consisting of:

-   -   (1) hydrogen,     -   (2) halogen,     -   (3) hydroxyl,     -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl or phenyl or napthyl, and     -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl or phenyl.

An embodiment of the present invention includes compounds wherein R^(2a), R^(2b) and R^(2c) are independently selected from the group consisting of:

-   -   (1) hydrogen,     -   (2) methyl,     -   (3) ethyl,     -   (4) trifluromethyl, and     -   (5) methoxy.

An embodiment of the present invention includes compounds wherein R^(2a) and R^(2b) are joined together to form a phenyl, pyridyl or piperidinyl ring.

An embodiment of the present invention includes compounds wherein R³ and R⁴ are independently selected from the group consisting of

-   -   (1) hydrogen, and     -   (2) C₁₋₆alkyl, which is unsubstituted or substituted with R¹⁴,     -   or R³ and R⁴ may be joined together to form a heterocyclyl,         which is unsubstituted or substituted with halogen, hydroxyl,         —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted         with halogen, hydroxyl or phenyl.

An embodiment of the present invention includes compounds wherein R³ and R⁴ are joined together to form a pyrrolopyridinyl, tetrahydronapthyridinyl, tetrahydropryido-napthyridinyl, or morpholinyl ring, which is unsubstituted or substituted with a substituent selected from the group consisting of:

-   -   (1) halogen,     -   (2) hydroxyl,     -   (3) pyridyl,     -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl or phenyl, and     -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl or phenyl.

An embodiment of the present invention includes compounds wherein R³ and R⁴ are joined together to form a tetrahydronapthyridinyl ring. An embodiment of the present invention includes compounds wherein R³ and R⁴ are joined together to form a morpholinyl ring.

Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

As appreciated by those of skill in the art, halogen or halo as used herein are intended to include fluorine, chlorine, bromine and iodine. Similarly, “alkyl”, as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof. C₁₋₆, as in C₁₋₆alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like. “Alkylene” means a straight or branched chain of carbon atoms with a group substituted at both ends, such as —CH₂CH₂— and —CH₂CH₂CH₂—. “Alkenyl” means a carbon chain which contains at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof such that C₂₋₆alkenyl is defined to identify the group as having 2, 3, 4, 5 or 6 carbons which incorporates at least one double bond, which may be in a E- or a Z-arrangement, including vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. “Alkynyl” means a carbon chain which contains at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof, such as ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. “Cycloalkyl” means a mono-, bi- or tri-cyclic structure, optionally combined with linear or branched structures, having the indicated number of carbon atoms, such as cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-1-bicyclo[4.4.0]decyl, and the like. “Alkoxy” means an alkoxy group of a straight or branched chain having the indicated number of carbon atoms. C₁₋₆alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like. The term “heterocyclyl” as used herein includes both unsaturated heterocyclic moieties comprising a mono- or bicyclic aromatic rings with at least one ring containing a heteroatom selected from N, O and S, and each ring containing 5 or 6 atoms (i.e. “heteroaryl”) and saturated heterocyclic moieties comprising mono- or bicyclic saturated rings with at least one ring containing a heteroatom selected from N, O and S, and each ring containing 3, 5 or 6 atoms. Examples of “heteroaryl” include benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, furo(2,3-b)pyridyl, imidazolyl, indolinyl, indolyl, dihydroindolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, pyrrolopyridinyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydronapthyridinyl, tetrahydropryidonapthyridinyl, tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof. Examples of saturated heterocyclic moieties (“saturated heterocycle”) include azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.

A group which is designated as being substituted with substituents may be substituted with multiple numbers of such substituents. A group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.

The compounds of the present invention may contain one or more stereogenic centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Any formulas, structures or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion. When stereochemistry is specified, the invention is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion.

The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

In the compounds of generic formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (¹H) and deuterium (²H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.

It will be understood that, as used herein, references to the compounds of present invention are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or in other synthetic manipulations. The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, cupric, cuprous, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like salts. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particular embodiments citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the pharmaceutically acceptable salts.

Exemplifying the invention are the specific compounds disclosed in the Examples and herein. The subject compounds are useful in a method of treating a neurological or psychiatric disorder associated with PDE10 dysfunction in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention. The subject compounds are useful in a method of inhibiting PDE10 activity in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. The subject compounds are also useful for treating a neurological or psychiatric disorder associated with striatal hypofunction or basal ganglia dysfunction in a mammalian patient in need thereof. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention.

The present invention is directed to a compound of the present invention or a pharmaceutically acceptable salt thereof for use in medicine. The present invention is further directed to a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a neurological or psychiatric disorder associated with PDE10 dysfunction in a mammalian patient in need thereof. The present invention is further directed to a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a neurological or psychiatric disorder associated with striatal hypofunction or basal ganglia dysfunction in a mammalian patient in need thereof.

“Treating” or “treatment of” a disease state includes: 1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state; 2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms; 3) or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

The subject treated in the present methods is generally a mammal, in particular, a human being, male or female, in whom therapy is desired. The term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with such disorders with an effective amount of the compound of the present invention. As used herein, the terms “treatment” and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy to retard the progression or reduce the risk of the noted conditions, particularly in a patient who is predisposed to such disease or disorder.

Applicants propose that inhibitors of PDE10 and, in particular inhibitors of PDE10A, will provide therapeutic benefit to those individuals suffering from psychiatric and cognitive disorders. The unique and exclusive distribution of PDE10A in the medium spiny projection neurons of the striatum, which form the principle site for cortical and dopaminergic input within basal ganglia, suggests that it may be possible and desirable to identify inhibitors of PDE10 to ameliorate or eliminate unwanted cellular signaling within this site. Without wishing to be bound by any theory, Applicants believe that inhibition of PDE10A in the striatum will result in increased cAMP/cGMP signaling and striatal output, which has the potential to restore behavioral inhibition that is impaired in cognitive disease such as schizophrenia. Regulation and integration of glutamatergic and dopaminergic inputs will enhance cognitive behavior, while suppressing or reducing unwanted behavior. Thus, in one embodiment, compounds of the invention provide a method for treating or ameliorating diseases or conditions in which striatal hypofunction is a prominent feature or ones in which basal ganglia dysfunction plays a role, such as, Parkinson's disease, Huntington's disease, schizophrenia, obsessive-compulsive disorders, addiction and psychosis. Other conditions for which the inhibitors described herein may have a desirable and useful effect include those requiring a reduction in activity and reduced response to psychomotor stimulants or where it would be desirable to reduce conditional avoidance responses, which is often predictive of clinical antipsychotic activity.

As used herein, the term “selective PDE 10 inhibitor” refers to an organic molecule that effectively inhibits an enzyme from the PDE10 family to a greater extent than enzymes from the PDE 1-9 or PDE11 families. In one embodiment, a selective PDE10 inhibitor is an organic molecule having a Ki for inhibition of PDE10 that is less than or about one-tenth that for a substance that is an inhibitor for another PDE enzyme. In other words, the organic molecule inhibits PDE10 activity to the same degree at a concentration of about one-tenth or less than the concentration required for any other PDE enzyme. Preferably, a selective PDE10 inhibitor is an organic molecule, having a Ki for inhibition of PDE10 that is less than or about one-hundredth that for a substance that is an inhibitor for another PDE enzyme. In other words, the organic molecule inhibits PDE10 activity to the same degree at a concentration of about one-hundredth or less than the concentration required for any other PDE enzyme. A selective PDE10 inhibitor can be identified, for example, by comparing the ability of an organic molecule to inhibit PDE 10 activity to its ability to inhibit PDE enzymes from the other PDE families. For example, an organic molecule may be assayed for its ability to inhibit PDE 10 activity, as well as PDE1A, PDE1B, PDE1C, PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, and/or PDE11A.

Phosphodiesterase enzymes including PDE10 have been implicated in a wide range of biological functions. This has suggested a potential role for these enzymes in a variety of disease processes in humans or other species. The compounds of the present invention have utility in treating a variety of neurological and psychiatric disorders.

In a specific embodiment, compounds of the present invention provide a method for treating schizophrenia or psychosis comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington D.C.) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorders. As used herein, the term “schizophrenia or psychosis” includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, conditions or diseases such as schizophrenia or psychosis, including schizophrenia (paranoid, disorganized, catatonic, undifferentiated, or residual type), schizophreniform disorder, schizoaffective disorder, for example of the delusional type or the depressive type, delusional disorder, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, phencyclidine, ketamine and other dissociative anaesthetics, and other psychostimulants), psychosispsychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, “schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, personality disorder of the paranoid type, personality disorder of the schizoid type, illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), including both the positive and the negative symptoms of schizophrenia and other psychoses.

In another specific embodiment, the compounds of the present invention provide a method for treating cognitive disorders comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The DSM-IV-TR also provides a diagnostic tool that includes cognitive disorders including dementia, delirium, amnestic disorders and age-related cognitive decline. As used herein, the term “cognitive disorders” includes the diagnosis and classification of these disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, disorders that comprise as a symptom a deficiency in attention and/or cognition, such as dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, intracranial tumors, cerebral trauma, vascular problems or stroke, alcoholic dementia or other drug-related dementia, AIDS, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse), Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal dementia, delirium, amnestic disorders or age related cognitive decline.

In another specific embodiment, compounds of the present invention provide a method for treating anxiety disorders comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The DSM-IV-TR also provides a diagnostic tool that includes anxiety disorders as generalized anxiety disorder, obsessive-compulsive disorder and panic attack. As used herein, the term “anxiety disorders” includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, anxiety disorders such as, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition.

In another specific embodiment, compounds of the present invention provide a method for treating substance-related disorders and addictive behaviors comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The DSM-IV-TR also provides a diagnostic tool that includes persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder induced by substance abuse, and tolerance of, dependence on or withdrawal from substances of abuse. As used herein, the term “substance-related disorders and addictive behaviors” includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, substance-related disorders and addictive behaviors, such as substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder, drug addiction, tolerance, and dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics.

In another specific embodiment, compounds of the present invention provide a method for treating obesity or eating disorders associated with excessive food intake, and complications associated therewith, comprising administering to a patient in need thereof an effective amount of a compound of the present invention. At present, obesity is included in the tenth edition of the International Classification of Diseases and Related Health Problems (ICD-10) (1992 World Health Organization) as a general medical condition. The DSM-IV-TR also provides a diagnostic tool that includes obesity in the presence of psychological factors affecting medical condition. As used herein, the term “obesity or eating disorders associated with excessive food intake” includes the diagnosis and classification of these medical conditions and disorders described in ICD-10 and DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, obesity, bulimia nervosa and compulsive eating disorders.

In another specific embodiment, compounds of the present invention provide a method for treating mood and depressive disorders comprising administering to a patient in need thereof an effective amount of a compound of the present invention. As used herein, the term “mood and depressive disorders” includes the diagnosis and classification of these medical conditions and disorders described in the DSM-FV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, bipolar disorders, mood disorders including depressive disorders, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode, a depressive episode with atypical features, a depressive episode with melancholic features, a depressive episode with catatonic features, a mood episode with postpartum onset, post-stroke depression; major depressive disorder, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, a bipolar disorder, for example, bipolar I disorder, bipolar II disorder, cyclothymic disorder, depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and substance-induced mood disorders.

In another specific embodiment, compounds of the present invention provide a method for treating pain comprising administering to a patient in need thereof an effective amount of a compound of the present invention. Particular pain embodiments are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain and neuropathic pain.

In other specific embodiments, compounds of the invention provide methods for treating other types of cognitive, learning and mental related disorders including, but not limited to, learning disorders, such as a reading disorder, a mathematics disorder, or a disorder of written expression, attention-deficit/hyperactivity disorder, age-related cognitive decline, pervasive developmental disorder including autistic disorder, attention disorders such as attention-deficit hyperactivity disorder (ADHD) and conduct disorder; an NMDA receptor-related disorder, such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury; a neurodegenerative disorder or condition, such as neurodegeneration associated with cerebral trauma, stroke, cerebral infarct, epileptic seizure, neurotoxin poisoning, or hypoglycemia-induced neurodegeneration; multi-system atrophy; movement disorders, such as akinesias and akinetic-rigid syndromes (including, Parkinson's disease, drug-induced parkinsonism, post-encephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), medication-induced parkinsonism (such as, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Huntington's disease, dyskinesia associated with dopamine agonist therapy, Gilles de la Tourette's syndrome, epilepsy, muscular spasms and disorders associated with muscular spasticity or weakness including tremors; dyskinesias, including tremor (such as, rest tremor, postural tremor, intention tremor and essential tremor), restless leg syndrome, chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including, generalised myoclonus and focal myoclonus), tics (including, simple tics, complex tics and symptomatic tics), dystonia (including, generalised, iodiopathic, drug-induced, symptomatic, paroxymal, and focal (such as blepharospasm, oromandibular, spasmodic, spasmodic torticollis, axial dystonia, hemiplegic and dystonic writer's cramp)); urinary incontinence; neuronal damage (including ocular damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and brain edema); emesis; and sleep disorders, including insomnia and narcolepsy.

Of the disorders above, the treatment of schizophrenia, bipolar disorder, depression, including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), learning disorders, pervasive developmental disorders, including autistic disorder, attention disorders including Attention-Deficit/Hyperactivity Disorder, autism, tic disorders including Tourette's disorder, anxiety disorders including phobia and post traumatic stress disorder, cognitive disorders associated with dementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment and loss are of particular importance.

The activity of the compounds in accordance with the present invention as PDE10 inhibitors may be readily determined without undue experimentation using a fluorescence polarization (FP) methodology that is well known in the art (Huang, W., et al., J. Biomol Screen, 2002, 7: 215). In particular, the compounds of the following examples had activity in reference assays by exhibiting the ability to inhibit the hydrolysis of the phosphosphate ester bond of a cyclic nucleotide. Any compound exhibiting a Ki (inhibitory constant) below 1 μM would be considered a PDE10 inhibitor as defined herein.

In a typical experiment the PDE10 inhibitory activity of the compounds of the present invention was determined in accordance with the following experimental method. PDE10A2 was amplified from human fetal brain cDNA (Clontech, Mountain View, Calif.) using a forward primer corresponding to nucleotides 56-77 of human PDE10A2 (Accession No. AF127480, Genbank Identifier 4894716), containing a Kozak consensus sequence, and a reverse primer corresponding to nucleotides 2406-2413 of human PDE10A2 (Accession No. AF127480, Genbank Identifier 4894716). Amplification with Easy-A polymerase (Stratagene, La Jolla, Calif.) was 95° C. for 2 minutes followed by thirty three cycles of 95° C. for 40 seconds, 55° C. for 30 seconds, and 72° C. for 2 minutes 48 seconds. Final extension was 72° C. for 7 minutes. The PCR product was TA cloned into pcDNA3.2-TOPO (Invitrogen, Carlsbad, Calif.) according to standard protocol. AD293 cells with 70-80% confluency were transiently transfected with human PDE10A2/pcDNA3.2-TOPO using Lipofectamine 2000 according to manufacturer specifications (Invitrogen, Carlsbad, Calif.). Cells were harvested 48 hours post-transfection and lysed by sonication (setting 3, 10×5 sec pulses) in a buffer containing 20 mM HEPES, 1 mM EDTA and protease inhibitor cocktail (Roche). Lysate was collected by centrifugation at 75,000×g for 20 minutes. Supernatant containing the cytoplasmic fraction was used for evaluation of PDE10A2 activity. The fluorescence polarization assay for cyclic nucleotide phosphodiesterases was performed using an IMAP® FP kit supplied by Molecular Devices, Sunnyvale, Calif. (product # R8139). IMAP® technology has been applied previously to phosphodiesterase assays (Huang, W., et al., J. Biomol Screen, 2002, 7: 215). Assays were performed at room temperature in 384-well microtiter plates with an incubation volume of 20.2 μL. Solutions of test compounds were prepared in DMSO and serially diluted with DMSO to yield 8 μL of each of 10 solutions differing by 3-fold in concentration, at 32 serial dilutions per plate. 100% inhibition is determined using a known PDE10 inhibitor, which can be any compound that is present at 5,000 times its Ki value in the assay described as follows, such as papaverine (see Siuciak, et al. Neuropharmacology (2006) 51:386-396; Becker, et al. Behav Brain Res (2008) 186(2):155-60; Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3):785-795), 2-{4-[pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]phenoxymethyl}quinoline succinic acid or 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]quinoline succinic acid (see Schmidt, et al. J Pharmacol Exp Ther (2008) 325:681-690; Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3): 785-795). 0% of inhibition is determined by using DMSO (1% final concentrations). A Labcyte Echo 555 (Labcyte, Sunnyvale, Calif.) is used to dispense 200 nL from each well of the titration plate to the 384 well assay plate. A solution of enzyme (1/1600 dilution from aliquots; sufficient to produce 20% substrate conversion) and a separate solution of FAM-labeled cAMP PDE from Molecular Devices (product # R7506), at a final concentration of 50 nM are made in the assay buffer (10 mM Iris HCl, pH 7.2, 10 mM MgCl₂, 0.05% NaN₃ 0.01% Tween-20, and 1 mM DTT). The enzyme and the substrate are then added to the assay plates in two consecutive additions of 10 μL, and then shaken to mix. The reaction is allowed to proceed at room temperature for 30 minutes. A binding solution is then made from the kit components, comprised of 80% Solution A, 20% Solution B and binding reagent at a volume of 1/600 the total binding solution. The enzymatic reaction is stopped by addition of 60 μL of the binding solution to each well of the assay plates and the plates are sealed and shaken for 10 seconds. The plate was incubated at room temperature for at least one hour prior to determining the fluorescence polarization (FP). The parallel and perpendicular fluorescence of each well of the plate was measured using a Perkin Elmer EnVision™ plate reader (Waltham, Mass.).

Fluorescence polarization (mP) was calculated from the parallel (S) and perpendicular (P) fluorescence of each sample well and the analogous values for the median control well, containing only substrate (So and Po), using the following equation: Polarization (mP)=1000*(S/So−P/Po)/(S/So+P/Po).

Dose-inhibition profiles for each compound were characterized by fitting the mP data to a four-parameter equation given below. The apparent inhibition constant (K_(I)), the maximum inhibition at the low plateau relative to “100% Inhibition Control” (Imax; e.g. 1=>same as this control), the minimum inhibition at the high plateau relative to the “0% Inhibition Control” (Imin, e.g. 0=> same as the no drug control) and the Hill slope (nH) are determined by a non-linear least squares fitting of the mP values as a function of dose of the compound using an in-house software based on the procedures described by Mosser et al., JALA, 2003, 8: 54-63, using the following equation:

${mP} = {\frac{\left( {{0\%\mspace{14mu}{mP}} - {100\%\mspace{14mu}{mP}}} \right)\left( {{Imax} - {Imin}} \right)}{1 + \left\lbrack \frac{\lbrack{Drug}\rbrack}{\left( {10^{- {pK}_{1}}\left( {1 + \frac{\lbrack{Substrate}\rbrack}{K_{M}}} \right)} \right.} \right\rbrack^{nH}} + {100\%\mspace{14mu}{mP}} + {\left( {{0\%\mspace{14mu}{mP}} - {100\%\mspace{14mu}{mP}}} \right)\left( {1 - {Imax}} \right)}}$

The median signal of the “0% inhibition controls” (0% mP) and the median signal of the “100% inhibition controls” (100% mP) are constants determined from the controls located in columns 1-2 and 23-24 of each assay plate. An apparent (K_(m)) for PAM-labeled cAMP of 150 nM was determined in separate experiments through simultaneous variation of substrate and selected drug concentrations.

Selectivity for PDE10, as compared to other PDE families, was assessed using the IMAP® technology. Rhesus PDE2A3 and Human PDE10A2 enzyme was prepared from cytosolic fractions of transiently transfected HEK cells. All other PDE's were GST Tag human enzyme expressed in insect cells and were obtained from BPS Bioscience (San Diego, Calif.): PDE1A (Cat#60010), PDE3A (Cat#60030), PDE4AIA (Cat#60040), PDE5A1 (Cat#60050), PDE6C (Cat#60060), PDE7A (Cat#60070), PDE8A1 (Cat#60080), PDE9A2 (Cat#60090), PDE11A4 (Cat#60110).

Assays for PDE 1 through 11 were performed in parallel at room temperature in 384-well microtiter plates with an incubation volume of 20.2 μL. Solutions of test compounds were prepared in DMSO and serially diluted with DMSO to yield 30 μL of each of ten solutions differing by 3-fold in concentration, at 32 serial dilutions per plate. 100% inhibition was determined by adding buffer in place of the enzyme and 0% inhibition is determined by using DMSO (1% final concentrations). A Labcyte POD 810 (Labcyte, Sunnyvale, Calif.) was used to dispense 200 nL from each well of the titration plate to make eleven copies of the assay plate for each titration, one copy for each PDE enzyme. A solution of each enzyme (dilution from aliquots, sufficient to produce 20% substrate conversion) and a separate solution of FAM-labeled cAMP or FAM-labeled cGMP from Molecular Devices (Sunnyvale, Calif., product # R7506 or cGMP#R7508), at a final concentration of 50 nM were made in the assay buffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl₂, 0.05% NaN₃ 0.01% Tween-20, and 1 mM DTT). Note that the substrate for PDE2 is 50 nM FAM cAMP containing 1000 nM of cGMP. The enzyme and the substrate were then added to the assay plates in two consecutive additions of 10 μL and then shaken to mix. The reaction was allowed to proceed at room temperature for 60 minutes. A binding solution was then made from the kit components, comprised of 80% Solution A, 20% Solution B and binding reagent at a volume of 1/600 the total binding solution. The enzymatic reaction was stopped by addition of 60 μL of the binding solution to each well of the assay plate. The plates were sealed and shaken for 10 seconds. The plates were incubated at room temperature for one hour, then the parallel and perpendicular fluorescence was measured using a Tecan Genios Pro plate reader (Tecan, Switzerland). The apparent inhibition constants for the compounds against all 11 PDE's was determined from the parallel and perpendicular fluorescent readings as described for PDE10 FP assay using the following apparent K_(M) values for each enzyme and substrate combination: PDE1A (FAM cGMP) 70 nM, rhesus PD2A3 (FAM cAMP) 10,000 nM, PDE3A (FAM cAMP) 50 nM, PDE4A1A (FAM cAMP) 1500 nM, PDE5A1 (FAM cGMP) 400 nM, PDE6C (FAM cGMP) 700 nM, PDE7A (FAM cAMP) 150 nM, PDE8A1 (FAM cAMP) 50 nM, PDE9A2 (PAM cGMP) 60 nM, PDE10A2 (FAM cAMP) 150 nM, PDE11A4 (FAM cAMP) 1000 nM. The intrinsic PDE10 inhibitory activity of a compound which may be used in accordance with the present invention may be determined by these assays.

The compounds of the following examples had activity in inhibiting the human PDE10 enzyme in the aforementioned assays, generally with an Ki of less than about 1 μM. Many of compounds within the present invention had activity in inhibiting the human PDE10 enzyme in the aforementioned assays, generally with an Ki of less than about 0.1 μM. Additional data is provided in the following Examples. Such a result is indicative of the intrinsic activity of the compounds in use as inhibitors of the PDE10 enzyme. In general, one of ordinary skill in the art would appreciate that a substance is considered to effectively inhibit PDE10 activity if it has a Ki of less than or about 1 μM, preferably less than or about 0.1 μM. The present invention also includes compounds within the generic scope of the invention which possess activity as inhibitors of other phosphodiesterase enzymes.

The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention may be desirable. However, the combination therapy may also includes therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, such as about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

Accordingly, the subject compounds may be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention. The subject compound and the other agent may be co-administered, either in concomitant therapy or in a fixed combination.

In one embodiment, the subject compound may be employed in combination with anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen, vitamin E, and anti-amyloid antibodies.

In another embodiment, the subject compound may be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, atypical antipsychotics, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, or the subject compound may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form.

In another embodiment, the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with the subject compound may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flutphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form. Thus, the subject compound may be employed in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.

In another embodiment, the subject compound may be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, a-adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists or antagonists, especially 5-HT_(1A) partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.

The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans. The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.

The term “composition” as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by mixing a compound of the present invention and a pharmaceutically acceptable carrier.

Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions, oily suspensions, dispersible powders or granules, oil-in-water emulsions, and sterile injectable aqueous or oleagenous suspension may be prepared by standard methods known in the art. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize. Generally, dosage levels of between 0.001 to 10 mg/kg. of body weight daily are administered to the patient, e.g., humans and elderly humans. The dosage range will generally be about 0.5 mg to 1.0 g. per patient per day which may be administered in single or multiple doses. In one embodiment, the dosage range will be about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; and in yet another embodiment about 5 mg to 50 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.

Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials and the requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures or as illustrated herein. The compounds of this invention may be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures. Substituent numbering as shown in the schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound where multiple substituents are allowed under the definitions hereinabove. Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the schemes and examples herein, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Starting materials are made according to procedures known in the art or as illustrated herein. The following abbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl; Cbz: benzyl carbamate; THF: tetrahydrofuran; Boc: tert-butyloxycarbonyl; DIPEA: N,N-diisopropylethylamine; DPPA: diphenylphosphorylazide; DMAP: 4-dimethylaminopyridine; DMSO: dimethylsulfoxide; EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; EtOAc: ethyl acetate; HOAt: 1-hydroxy-7-azabenzotriazole; HOBt: hydroxybenzotriazole hydrate; TEA: triethylamine; DMF: N,N-dimethylformamide; rt: room temperature; HPLC: high performance liquid chromatography; NMR: nuclear magnetic resonance; TLC: thin-layer chromatography.

In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully-understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

Hydroxymethyl pyridine derivatives can be readily converted to their corresponding chloromethyl pyridyl HCl salts (A-1) by treatment with thionyl chloride. Alkylation of commercially available phenolic boronate esters with A-1 under standard conditions provides elaborated boronate esters A-2.

Highly selective C—N cross couplings of variably functionlized 2-chloro-3-iodopyridines with a variety of primary and secondary amines furnishes 2-chloro-3-aminopyridines B-1. High-yielding Suzuki cross couplings with A-2 under standard conditions furnishes the fully elaborated products of the formula B-2 of the present invention.

The synthetic scheme outlined in Generic Scheme B can be readily applied to any chloro-iodopyridine isomer to furnish all possible regioisomeric pyridine backbones of the current invention. As illustrated in Generic Scheme C, 3-iodo-4-chloropyridine can be used under otherwise identical conditions to furnish fully elaborated products of the formula C-2. 3-chloro-4-iodopyridine and 2-iodo-3-chloropyridine can be used analogously.

A pyrazine group can be incorporated through a tandem SNAr/Suzuki protocol. Beginning with commercially available dichloropyrazine, a variety of primary and secondary amines can be added to furnish the corresponding 2-chloro-3-amino-pyrazines. These intermediate products can be isolated, or used directly in a one-pot procedure. As such, boronate esters of the form A-2 can be coupled to afford products of the formula D-1 of the present invention.

Example 1

2-(chloromethyl)-3,4-dimethoxypyridine hydrochloride (1-1)

A solution of (3,4-dimethoxypyridin-2-yl)methanol (1 g, 5.91 mmol) in CH₂CH₂ (11.82 mL) was treated dropwise with thionyl chloride (1 mL, 13.70 mmol) with stirring at room temperature. The reaction mixture was stirred for 2 h, and then concentrated directly in vacuo. The resulting residue was washed with 3×10 mL Et₂O, the resulting solids collected by filtration, and then dried under reduced pressure to afford the title compound as a white solid (1.12 g, 85%), which was used in the subsequent step without further purification. Data for 1-1: LC/MS: rt=0.58 min, m/z (M+H)=188.09 found; 188.04 required. 3,4-dimethoxy-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-pyridine (1-2)

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (100 mg, 0.454 mmol), 1-1 (85 mg, 0.454 mmol), and K₂CO₃ (157 mg, 1.136 mmol) were combined in a 50-mL round bottom flask with a stirbar. DMF (3.03 mL) was added, and the reaction mixture was heated to 90° C. for 4 h. The reaction mixture was diluted with EtOAc (30 mL), and washed sequentially with sat. aq. NaHCO₃ (30 mL) and brine (30 mL). The combined organics were dried over MgSO₄, filtered, and concentrated in vacuo to afford the title compound as a tan solid (155 mg, 78%, >85% pure), which was used in the subsequent step without further purification. Data for 1-2: LC/MS: rt=1.78 min, m/z (M+H)=372.19 found; 372.19 required.

Example 2

4-(2-chloropyridin-3-yl)morpholine (2-1)

A 2-dram vial equipped with a stirbar was charged with Pd(OAc)₂ (0.234 g, 1.044 mmol) and rac-BINAP (0.683 g, 1.096 mmol) as solids. Toluene (4 mL) was added via syringe, and the mixture was stirred for 10 min while being degassed with argon, and until a uniform tan suspension resulted. A 100-mL round-bottom flask was charged with 2-chloro-3-iodopyridine (1.25 g, 5.22 mmol) and Cs₂CO₃ (7.14 g, 21.93 mmol). Toluene (34.8 mL) was added followed by morpholine (0.542 ml, 6.26 mmol). This solution was degassed for 1 min under argon, and then the catalyst/ligand suspension was added via pasteur pipette. A reflux condenser was attached to the flask, and the reaction mixture was refluxed at 120° C. for 16 h. The reaction mixture was concentrated in vacuo, and then diluted with CH₂Cl₂ (150 mL). The organics were washed with 2×100 mL brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The material was purified by gradient elution on silica gel (5 to 75% [5% MeOH/EtOAc] in hexanes) to afford the title compound as light yellow solid (700 mg, 64%). Data for 2-1: ¹H NMR (500 MHz, CDCl₃) d 8.08 (dd, J=4.4, 1.5 Hz, 1H), 7.32 (dd, J=7.8, 1.5 Hz, 1H), 7.21 (dd, J=7.8, 4.5 Hz, 1H), 3.89 (dd, J=4.5, 4.5 Hz, 4H), 3.08 (dd, J=4.5, 4.5 Hz, 4H); HRMS m/z (M+H) 199.0630 found, 199.0633 required.

4-(2-{4-[(3,4-dimethoxypyridin-2-yl)methoxy]phenyl}pyridin-3-yl)morpholine (2-2)

A solution of 2-2 (28.0 mg, 0.076 mmol) in DMF (378 μl) was degassed under argon for 5 min. Next, 2-1 (15 mg, 0.076 mmol), Pd(PPh₃)₄ (17.45 mg, 0.015 mmol), and Cs₂CO₃ (61.5 mg, 0.189 mmol) were added in one portion as solids, and the reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was diluted with EtOAc (10 mL) and washed sequentially with sat. aq. NaHCO₃ (10 mL) and brine (10 mL). The combined organics were-dried over MgSO4, filtered, and concentrated in vacuo. The material was purified by gradient elution on silica gel (10 to 100% [5% MeOH/EtOAc] in hexanes) to afford the title compound as an off-white solid (21.3 mg, 65.8%). Data for 2-2: ¹H NMR (500 MHz, CDCl₃) d 8.32 (dd, J=4.6, 1.2 Hz, 1H), 8.30 (d, J=5.5 Hz, 1H), 7.93 (d, J=8.8 Hz, 2H), 7.29 (dd, J=8.1, 1.2 Hz, 1H), 7.15 (dd, J=8.1, 4.6 Hz, 1H), 7.10 (d, J=8.8 Hz, 2H), 6.86 (d, J=5.5 Hz, 1H), 5.24 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.68 (dd, J=4.6, 4.6, 4H), 2.85 (dd, J=4.6, 4.6 Hz, 4H); HRMS m/z (M+H) 408.1918 found, 408.1918 required.

Example 3

2-chloro-3-[3-(3-methylphenyl)piperidin-1-yl]pyridine (3-1)

Dichloropyrazine (100 mg, 0.454 mmol), 3-(3-methylphenyl)piperidine hydrochloride (85 mg, 0.454 mmol), and K₂CO₃ (157 mg, 1.136 mmol) were combined in a 25-mL round bottom flask with a stirbar. DMF (4.48 mL) was added, and the reaction mixture was heated to 50° C. for 4 h. The reaction mixture was diluted with EtOAc (20 mL), and washed sequentially with sat. aq. NaHCO₃ (20 mL) and brine (20 mL). The combined organics were dried over MgSO₄, filtered, and concentrated in vacuo to afford the title compound as a brown gum (155 mg, 76%), which was used in the subsequent step without further purification. Data for H-1: LC/MS: rt=3.17 min, m/z (M+H)=288.15 found; 288.79 required.

3,5-dimethoxy-4-methyl-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}pyridine (3-2)

The title compound was prepared according to the protocol described in Example 1, substituting the requisite starting materials. Data for 3-2: LC/MS: rt=1.77 min, m/z (M+H)=370.18 found; 370.26 required.

2-{4-[(3,5-dimethoxy-4-methylpyridin-2-yl)methoxy]phenyl}-3-[3-(3-methylphenyl)-piperidin-1-yl]pyrazine (3-3)

A solution of H-1 (25.0 mg, 0.087 mmol) in DMF (579 μl) was degassed under argon for 5 min. Next, H-2 (32.1 mg, 0.087 mmol), Pd(PPh₃)₄ (20.1 mg, 0.017 mmol), and Cs₂CO₃ (70.8 mg, 0.217 mmol) were added in one portion as solids, and the reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was diluted with EtOAc (10 mL) and washed sequentially with sat. aq. NaHCO₃ (10 mL) and brine (10 mL). The combined organics were dried over MgSO₄, filtered, and concentrated in vacuo. The material was purified by gradient elution on silica gel (10 to 50% [5% MeOH/EtOAc] in hexanes) to afford the title compound as a white solid (19.5 mg, 40.8%). Data for H-3: ¹H NMR (500 MHz, CDCl₃) d 8.25 (br s, 1H), 8.09 (d, J=2.6 Hz, 1H), 8.02 (d, J=2.6 Hz, 1H), 7.90 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 7.10-7.15 (m, 1H), 6.98-7.00 (m, 1H), 6.86-6.89 (m, 2H), 5.24 (s, 2H), 3.78 (s, 3H), 3.72 (dd, J=20.3, 14.4 Hz, 1H), 2.74-2.80 (m, 1H), 2.60-2.71 (m, 2H), 2.35 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H), 1.99 (br d, J=12.2 Hz, 1H), 1.58-1.78 (m, 4H); HRMS m/z (M+H) 495.2753 found, 495.2755 required.

TABLE 1 The following compounds were prepared using the foregoing methodology, but substituting the appropriately substituted reagent, as described in the foregoing Reaction Schemes and Examples. The requisite starting materials were commercially available, described in the literature, or readily synthesized by one skilled in the art of organic synthesis without undue experimentation. Final products were purified by either gradient elution on SiO₂ (EtOAc/hexanes or MeOH/CH₂Cl₂), reverse phase flash chromatography (MeCN/H₂O), or preparative thin layer chromatography (EtOAc/hexanes or MeOH/CH₂Cl₂ or MeOH/EtOAc), and were isolated as free-bases. Cpd. Structure Name HRMS m/z (M + H) 4

6-(3-{4-[(4-methoxy- 3,5-dimethylpyridin- 2-yl)-methoxy]- phenyl}pyridin-2-yl)- 5,6,7,8-tetrahydro- 1,6-naphthyridine 453.2288 found, 453.2285 required. 5

2-{4-[(4-methoxy- 3,5-dimethylpyridin-2- yl)methoxy]phenyl}- N-methyl-N-(pyridin- 4-ylmethyl)pyridin-3- amine 441.2287 found, 441.2285 required. 6

7-({4-[3-(2-pyridin- 3-ylmorpholin-4- yl)pyridin-2- yl]phenoxy}methyl)- 1,2,3,4-tetrahydro- 1,8-naphthyridine 480.2389 found, 480.2394 required. 7

N-(pyridin-4- ylmethyl)-2-[4- (5,6,7,8-tetrahydro- 1,8-naphthyridin-2- ylmethoxy)phenyl]- pyridin-3-amine 424.2128 found, 424.2132 required. 8

2-({4-[3-(3,4- dihydroisoquinolin- 2(1H)-yl)pyridin-2- yl]phenoxy}methyl)- quinoline 444.2067 found, 444.2070 required. 9

7-{2-[4-(quinolin-2- ylmethoxy)phenyl]- pyridin-3-yl}-6,7,8,9- tetrahydropyrido[2,3 - b]-1,6-naphthyridine HRMS m/z (M + H) 496.2116 found, 496.2132 required. 10

6-(2-{4-[(4-methoxy- 3,5-dimethylpyridin- 2-yl)methoxy]- phenyl}pyridin-3- yl)-5,6,7,8- tetrahydro-1,6- naphthyridine 453.2288 found, 453.2285 required. 11

N-ethyl-N-pyridin-3- yl-2-[4-(quinolin-2- ylmethoxy)phenyl]- pyridin-3-amine 433.2022 found, 433.2023 required. 12

2-({4-[3-(2-pyridin- 3-ylmorpholin-4- yl)pyridin-2- yl]phenoxy}methyl)- quinoline 475.2122 found, 475.2129 required. 13

4-(2-{3-chloro-5- methoxy-4-[(4- methoxy-3,5- dimethylpyridin-2- yl)methoxy]phenyl}- pyridin-3- yl)morpholine 470.1843 found, 470.1841 required. 14

2-({4-[3-(2,3- dihydro-1H- pyrrolo[2,3- c]pyridin-1- yl)pyridin-2- yl]phenoxy}- methyl)quinoline 431.1855 found, 431.1866 required. 1-5

6-(2-{4-[(6- methylpyridin-2- yl)methoxy]phenyl}- pyridin-3-yl)-3- (trifluoromethyl)- 5,6,7,8-tetrahydro- 1,6-naphthyridine 477.1901 found, 477.1897 required. 16

6-(5-fluoro-2-{4-[(4- methoxy-3,5- dimethylpyridin-2- yl)methoxy]phenyl}- pyridin-3-yl)-5,6,7,8- tetrahydro-1,6- naphthyridine 471.2178 found, 471.2191 required. 17

4-[2-(4-{[5- (trifluoromethyl)- pyridin-2- yl]methoxy}phenyl)- pyridin-3- yl]morpholine 416.1581 found, 416.1580 required. 18

6-{4-[4-(quinolin-2- ylmethoxy)phenyl]- pyridin-3-yl}-5,6,7,8- tetrahydro-1,6- naphthyridine HRMS m/z (M + H) 445.2022 found, 445.2023 required. 19

6-{3-[4-(5,6,7,8- tetrahydro-1,8- naphthyridin-2- ylmethoxy)phenyl]- pyrazin-2-yl}-5,6,7,8- tetrahydro-1,6- naphthyridine 451.2238 found, 451.2241 required.

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. 

1. A compound of the formula I:

wherein: X is —CH— or N, Y is —CH— or N, and Z is —CH— or N, with the proviso that at least one of X, Y and Z is N; R¹ is selected from the group consisting of: (1) hydrogen, (2) halogen, (4) C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl, or phenyl, and (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl; R^(2a), R^(2b) and R^(2c) are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl, phenyl or napthyl, (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, (6) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (7) heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (8) —O-phenyl, which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (10) —CO₂H, (11) —CN, and (12) —NO₂, or R^(2a) and R^(2b) may be joined together to form a phenyl, pyridyl or piperidinyl ring, which is unsubstituted or substituted with R^(2c); R³ and R⁴ are independently selected from the group consisting of: (1) hydrogen, and (2) C₁₋₆alkyl, which is unsubstituted or substituted with R¹⁴, or R³ and R⁴ may be joined together to form a heterocyclyl, which is unsubstituted or substituted with halogen, hydroxyl, phenyl, pyridyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl; R¹⁴ is selected from the group consisting of: (1) hydroxyl, (2) halogen, (3) C₁₋₆alkyl, (4) —C₃₋₆cycloalkyl, (5) —O—C₁₋₆alkyl, (6) —O(C═O)—C₁₋₆alkyl, (7) ═O, (8) —CO₂H, (9) —CO₂—C₁₋₆alkyl, (10) —NH(C═O)—C₁₋₆alkyl, —N(C₁₋₆alkyl)(C═O)—C₁₋₆alkyl, —NH(C═O)—O—C₁₋₆alkyl, —N(C₁₋₆alkyl)(C═O)—O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (11) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (12) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (13) heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (14) heterocyclyl, which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, and (15) —CN; or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1 wherein: X is N, Y is —CH—, and Z is —CH—; X is —CH—, Y is —N, and Z is —CH—; X is —CH—, Y is —CH—, and Z is N; or X is N, Y is —CH—, and Z is N.
 3. The compound of claim 1 wherein R¹ is selected from the group consisting of: (1) hydrogen, and (2) halogen.
 4. The compound of claim 2 wherein R^(2a), R^(2b) and R^(2c) are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl, phenyl or napthyl, (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, (6) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (7) heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (8) —O-phenyl, which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is unsubstituted or substituted with halogen, hydroxyl, —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (10) —CO₂H, (11) —CN, and (12) —NO₂, or R^(2a) and R^(2b) may be joined together to form a phenyl, pyridyl or piperidinyl ring, which is unsubstituted or substituted with R^(2c).
 5. The compound of claim 4 wherein R^(2a), R^(2b) and R^(2c) are independently selected from the group consisting of: (1) hydrogen, (2) methyl, (3) ethyl, (4) trifluoromethyl, and (5) methoxy.
 6. The compound of claim 4 wherein R^(2a) and R^(2b) are joined together to form a phenyl, pyridyl or piperidinyl ring.
 7. The compound of claim 1 wherein R³ and R⁴ are joined together to form a pyrrolopyridinyl, tetrahydronapthyridinyl, tetrahydropryido-napthyridinyl, or morpholinyl ring, which is unsubstituted or substituted with a substituent selected from the group consisting of: (1) halogen, (2) hydroxyl, (3) pyridyl, (4) C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl.
 8. The compound of claim 7 wherein R³ and R⁴ are joined together to form a tetrahydronapthyridinyl ring.
 9. The compound of claim 7 wherein R³ and R⁴ are joined together to form a morpholinyl ring.
 10. A compound which is selected from the group consisting of: 4-(2-{4-[(3,4-dimethoxypyridin-2-yl)methoxy]phenyl}pyridin-3-yl)morpholine; 2-{4-[(3,5-dimethoxy-4-methylpyridin-2-yl)methoxy]phenyl}-3-[3-(3-methylphenyl)-piperidin-1-yl]pyrazine; 6-(3-{4-[(4-methoxy-3,5-dimethylpyridin-2-yl)-methoxy]-phenyl}pyridin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 2-{4-[(4-methoxy-3,5-dimethylpyridin-2-yl)methoxy]phenyl}-N-methyl-N-(pyridin-4-ylmethyl)pyridin-3-amine; 7-({4-[3-(2-pyridin-3-ylmorpholin-4-yl)pyridin-2-yl]phenoxy}methyl)-1,2,3,4-tetrahydro-1,8-naphthyridine; N-(pyridin-4-ylmethyl)-2-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethoxy)phenyl]pyridin-3-amine; 2-({4-[3-(3,4-dihydroisoquinolin-2(1H)-yl)pyridin-2-yl]phenoxy}methyl)quinoline; 7-{2-[4-(quinolin-2-ylmethoxy)phenyl]pyridin-3-yl}-6,7,8,9-tetrahydropyrido[2,3-b]-1,6-naphthyridine; 6-(2-{4-[(4-methoxy-3,5-dimethylpyridin-2-yl)methoxy]phenyl}pyridin-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; N-ethyl-N-pyridin-3-yl-2-[4-(quinolin-2-ylmethoxy)phenyl]pyridin-3-amine; 2-({4-[3-(2-pyridin-3-ylmorpholin-4-yl)pyridin-2-yl]phenoxy}methyl)quinoline; 4-(2-{3-chloro-5-methoxy-4-[(4-methoxy-3,5-dimethylpyridin-2-yl)methoxy]phenyl}pyridin-3-yl)morpholine; 2-({4-[3-(2,3-dihydro-1H-pyrrolo [2,3-c]pyridin-1-yl)pyridin-2-yl]phenoxy}-methyl)quinoline; 6-(2-{4-[(6-methylpyridin-2-yl)methoxy]phenyl}pyridin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 6-(5-fluoro-2-{4-[(4-methoxy-3,5-dimethylpyridin-2-yl)methoxy]phenyl}pyridin-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 4-[2-(4-{[5-(trifluoromethyl)pyridin-2-yl]methoxy}phenyl)pyridin-3-yl]morpholine; 6-{4-[4-(quinolin-2-ylmethoxy)phenyl]pyridin-3-yl}-5,6,7,8-tetrahydro-1,6-naphthyridine; and 6-{3-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethoxy)phenyl]pyrazin-2-yl}-5,6,7,8-tetrahydro-1,6-naphthyridine; or a pharmaceutically acceptable salt thereof.
 11. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof. 